Metabolic systems analysis identifies a novel mechanism contributing to shock in patients with endotheliopathy of trauma (EoT) involving thromboxane A2 and LTC4

Henriksen, H; Mas, Igor Marín de; Herand, Helena; Krocker, Joseph; Wade, Charles E.; Johansson, Pär I.

doi:10.1016/j.mbplus.2022.100115

Cited by 6 publications

(24 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This work suggests a mechanism for the previously noted association between succinate levels and mortality in critically injured patients ( 24 ). A recent study suggests an association between glycocalyx shedding and plasma succinate levels which agrees with our findings ( 54 ).…”

Section: Discussionsupporting

confidence: 93%

“…This leads to an increase in colocalization and molecular interaction between the enzymes MMP24 and MMP25 with syndecan-1. This work suggests a mechanism for the previously noted association between altered lipid metabolism measured at admission and mortality or endotheliopathy in patients with trauma (54,57). This previously unknown effect on membrane organization could have implications beyond glycocalyx damage.…”

Section: Discussionmentioning

confidence: 61%

See 1 more Smart Citation

Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage

Abdullah,

Ghio,

Cotton-Betteridge

et al. 2023

Sci. Adv.

View full text Add to dashboard Cite

Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these adverse outcomes. The physiological events mediating acute glycocalyx shedding are undefined, however. Here, we show that succinate accumulation within endothelial cells drives glycocalyx degradation through a membrane reorganization-mediated mechanism. We investigated this mechanism in a cultured endothelial cell hypoxia-reoxygenation model, in a rat model of hemorrhage, and in trauma patient plasma samples. We found that succinate metabolism by succinate dehydrogenase mediates glycocalyx damage through lipid oxidation and phospholipase A2-mediated membrane reorganization, promoting the interaction of matrix metalloproteinase 24 (MMP24) and MMP25 with glycocalyx constituents. In a rat hemorrhage model, inhibiting succinate metabolism or membrane reorganization prevented glycocalyx damage and coagulopathy. In patients with trauma, succinate levels were associated with glycocalyx damage and the development of coagulopathy, and the interaction of MMP24 and syndecan-1 was elevated compared to healthy controls.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 61%

Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage

Abdullah,

Ghio,

Cotton-Betteridge

et al. 2023

Sci. Adv.

View full text Add to dashboard Cite

show abstract

“…The enzymatic activity of heparanase-1 is also reviewed by Pape et al, and the counterbalancing role of heparanase-2 to regulate or inhibit heparanase-1 activity is described [8] . Interestingly, an original research report by Henriksen et al, reveals that patients admitted with endotheliopathy of trauma (defined by shed syndecan-1 within the plasma of > 40 ng/ml) have detectable differences in metabolites within their plasma that suggests the possibility of impaired thromboxaneA2 and LTC4 synthesis [9] . Reduced thromboxaneA2 and leukotrienes impairs vasoconstriction leading the authors to speculate that these metabolic changes may contribute to endotheliopathy, shock and high mortality within this patient population.…”

Section: Glycocalyx Pathobiologymentioning

confidence: 99%

The glycocalyx: Pathobiology and repair

Richter

Sanderson

2023

Matrix Biology Plus

View full text Add to dashboard Cite

“…Bioengineering 2023, 10, x FOR PEER REVIEW 15 of 20 higher in THG (6.11), showing a more complete coverage of the relation between metabolism and gene regulatory mechanisms. A metabolic task analysis was also carried out on the models to determine if they were able to perform the essential metabolic functions necessary for cell viability [21,23]. The task list (see Supplementary Material File S4) was originally developed for the reference model, and the models in the THG series continued to be able to perform all the activities.…”

Section: Model Assessment Via Memote and Task Analysismentioning

confidence: 99%

“…GEMs have been used for a variety of applications [17], including studies of evolution [18], metabolic engineering [19], genome annotation [20], drug discovery [21] and systems medicine [22], among many others. Reconstructions of human metabolism such as Recon3D [23], HMR2 [24] or the most recent reconstruction of human metabolism, Human1 [25], have been widely used to decipher the mechanism underlying diseases with a strong metabolic component, such as cancer or diabetes, in the context of systems biology, as well as to improve industrial processes involving human cell lines such as Hek293 [26].…”

Section: Introductionmentioning

confidence: 99%

A Protocol for the Automatic Construction of Highly Curated Genome-Scale Models of Human Metabolism

et al. 2023

Self Cite

View full text Add to dashboard Cite

Genome-scale metabolic models (GEMs) have emerged as a tool to understand human metabolism from a holistic perspective with high relevance in the study of many diseases and in the metabolic engineering of human cell lines. GEM building relies on either automated processes that lack manual refinement and result in inaccurate models or manual curation, which is a time-consuming process that limits the continuous update of reliable GEMs. Here, we present a novel algorithm-aided protocol that overcomes these limitations and facilitates the continuous updating of highly curated GEMs. The algorithm enables the automatic curation and/or expansion of existing GEMs or generates a highly curated metabolic network based on current information retrieved from multiple databases in real time. This tool was applied to the latest reconstruction of human metabolism (Human1), generating a series of the human GEMs that improve and expand the reference model and generating the most extensive and comprehensive general reconstruction of human metabolism to date. The tool presented here goes beyond the current state of the art and paves the way for the automatic reconstruction of a highly curated, up-to-date GEM with high potential in computational biology as well as in multiple fields of biological science where metabolism is relevant.

show abstract

Metabolic systems analysis identifies a novel mechanism contributing to shock in patients with endotheliopathy of trauma (EoT) involving thromboxane A2 and LTC4

Cited by 6 publications

References 60 publications

Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage

Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage

The glycocalyx: Pathobiology and repair

A Protocol for the Automatic Construction of Highly Curated Genome-Scale Models of Human Metabolism

Contact Info

Product

Resources

About